Genomic surveillance as a scalable framework for precision phage therapy against antibiotic-resistant pathogens.

Phage therapy is gaining increasing interest in the fight against critically antibiotic-resistant nosocomial pathogens. However, the narrow host range of bacteriophages hampers the development of broadly effective phage therapeutics and demands precision approaches. Here, we combine large-scale phylogeographic analysis with high-throughput phage typing to guide the development of precision phage cocktails targeting carbapenem-resistant Acinetobacter baumannii, a top-priority pathogen. Our analysis reveals that a few strain types dominate infections in each world region, with their geographical distribution remaining stable within 6 years. As we demonstrate in Eastern Europe, this spatiotemporal distribution enables preemptive preparation of region-specific phage collections that target most local infections. Finally, we showcase the efficacy of phage cocktails against prevalent strain types using in vitro and animal infection models. Ultimately, genomic surveillance identifies patients benefiting from the same phages across geographical scales, thus providing a scalable framework for precision phage therapy.

Matching the pitch perception of the cochlear implanted ear with the contralateral ear in patients with single-sided deafness: a novel approach.

PURPOSE: Single-sided deaf patients following cochlear implantation often compare the sound quality of their implanted ear with normal hearing. The interaural differences can result in dissatisfaction with speech comprehension and reduced time of usage of the speech processor; hence, prolonging auditory adaptation time. The proposed calibration method presented in this study demonstrates how the frequency distribution of the cochlear implant can be set to adequately approximate the pitch perception of the contralateral normal hearing ear towards improving speech intelligibility in a noisy environment. METHODS: In 12 postlingual single-sided deaf patients, subjective interaural pitch-matching was carried out to determine new central frequencies for the reallocation of the frequency bands of their speech processor (CP910, CP950 or CP1000, Cochlear, Australia). The patients were asked to compare the pitch of the tones presented to their normal hearing ear to the pitch of individual channels of their cochlear implant (CI522 or CI622, Cochlear, Australia). A third-degree polynomial curve was fit to the acquired matching frequencies to create the new frequency allocation table. Audiological measurements (free-field aided thresholds, speech reception thresholds, and monosyllabic word recognition score) in noise, together with a Speech, Spatial and Qualities of Hearing Scale (SSQ12) questionnaire (short version of the original SSQ) results were evaluated prior to the pitch-matching procedure, and again, 2 weeks later. RESULTS: The free-field aided thresholds of the patients showed no greater shift than ± 5 dB following the procedure; however, their monosyllabic word recognition score in noise improved significantly (mean - 9.58%, SD 4.98%, matched pairs t test comparison: p < 0.001). The results of the SSQ12 questionnaire also showed significant improvement in speech intelligibility, sound localization, and sound quality (mean 0.96 points, SD 0.45 points, matched pairs t test comparison: p < 0.001). CONCLUSIONS: Matching the pitch perception of the implanted cochlea with the sensation of the normal hearing contralateral ear, resulted in significant changes in the quality of hearing in patients with single-sided deafness. It is plausible the procedure can usher positive results in bimodal patients or following sequential bilateral cochlear implantation.

An appraisal: how notifiable infectious diseases are reported by Hungarian family physicians.

BACKGROUND: Within the frame of National Epidemiological Surveillance System, family physicians have an obligation to report infections and suspicions cases. The aim of this study was to evaluate the knowledge, attitudes, daily practice and the reporting activities of Hungarian family physicians regarding to infectious diseases. METHODS: A self-administered survey was developed, validated and used. The survey was completed by family physicians who had taken part in continuous medical educational programmes of all Hungarian medical faculties. The questionnaire, consisting demographic questions and 10 statements about their reporting habits were completed by 347 doctors, 8% of the total number of family physicians. The data were processed in a cross-sectional design with general linear model. RESULTS: According to the majority of responders, the current reporting system works efficiently. Rural physicians were mainly agreed, that reporting is not a simply obligation, it is a professional task as well. They were less hindered in daily work by reporting activities, waited less for laboratory confirmation before reporting, reported suspicious cases more frequently. Practitioner's based in urban settlements preferred to await laboratory tests before reporting and were hindered less by failures of the electronic reporting system. Older physicians trusted more in the recent system and they wished to increase the number of reports. Female physicians have higher consciousness in epidemiology. They were mostly in agreement that even severe infectious diseases can be diagnosed at primary care level and their daily practices were less burdened by reporting duties. CONCLUSIONS: Both the epidemiological knowledge of general practitioners' and the electronic surveillance systems should be improved. There is a need to develope the electronic infrastructure of primary care. More and regular control is also expected by the health care authorities, beside the synthesis of professional and governmental expectations and regulations.

[Pneumococcal vaccination in general practice]. / A pneumococcusvakcináció gyakorlata a családorvosi praxisokban.

INTRODUCTION: The prevalence of invasive pneumococcal disease, which is depending on risk factors and comorbidities, is increasing over the age of 50 years. Most developed countries have recommendations but vaccination rates remain low. AIM: To assess the general practitioners' daily practice in relation to pneumococcal vaccination and analyse the effect of informing the subjects about the importance of pneumococcal vaccination on vaccination routine. METHOD: Subjects over 50 years of age vaccinated against influenza during the 2012/2013 campaign were informed about the importance of pneumococcal vaccination and asked to fill in a questionnaire. RESULTS: Of the 4000 subjects, 576 asked for a prescription of pneumococcal vaccine (16.5% of females and 11.6% of males, OR 1.67 CI 95% 1.37-2.04, p<0.001) and 310 were vaccinated. The mean age of females and males was 70.95 and 69.8 years, respectively (OR 1.01; CI 95% 1.00-1.02; p<0.05). Information given by physicians resulted in 33,6% prescription rate, while in case it was 8% when nurses provided information (OR 6.33; CI 95% 5.23-7.67; p<0.001). As an effect of this study the vaccination rate was 6.3 times higher than in the previous year campaign (p<0.001). CONCLUSIONS: General practitioners are more effective in informing subjects about the importance of vaccination than nurses. Campaign can raise the vaccination rate significantly.

ChatGPT M.D.: Is there any room for generative AI in neurology?

ChatGPT, a general artificial intelligence, has been recognized as a powerful tool in scientific writing and programming but its use as a medical tool is largely overlooked. The general accessibility, rapid response time and comprehensive training database might enable ChatGPT to serve as a diagnostic augmentation tool in certain clinical settings. The diagnostic process in neurology is often challenging and complex. In certain time-sensitive scenarios, rapid evaluation and diagnostic decisions are needed, while in other cases clinicians are faced with rare disorders and atypical disease manifestations. Due to these factors, the diagnostic accuracy in neurology is often suboptimal. Here we evaluated whether ChatGPT can be utilized as a valuable and innovative diagnostic augmentation tool in various neurological settings. We used synthetic data generated by neurological experts to represent descriptive anamneses of patients with known neurology-related diseases, then the probability for an appropriate diagnosis made by ChatGPT was measured. To give clarity to the accuracy of the AI-determined diagnosis, all cases have been cross-validated by other experts and general medical doctors as well. We found that ChatGPT-determined diagnostic accuracy (ranging from 68.5% ± 3.28% to 83.83% ± 2.73%) can reach the accuracy of other experts (81.66% ± 2.02%), furthermore, it surpasses the probability of an appropriate diagnosis if the examiner is a general medical doctor (57.15% ± 2.64%). Our results showcase the efficacy of general artificial intelligence like ChatGPT as a diagnostic augmentation tool in medicine. In the future, AI-based supporting tools might be useful amendments in medical practice and help to improve the diagnostic process in neurology.

Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009-10 influenza season: a multicentre, randomised controlled trial.

BACKGROUND: With the ongoing 2009 pandemic of influenza A H1N1, development of pandemic influenza vaccines has generated much interest. We investigated the safety and immunogenicity of a whole-virion, inactivated, adjuvanted pandemic H1N1 vaccine in adult and elderly volunteers, given without or simultaneously with the 2009-10 seasonal trivalent influenza vaccine. METHODS: This prospective, randomised study was undertaken in two centres in Hungary. 355 participants, including 203 adults (18-60 years) and 152 elderly people (>60 years), were assigned by stratified randomisation to either 0.5 mL of the pandemic vaccine (Fluval P, a monovalent vaccine with 6 microg haemagglutinin per 0.5 mL content and aluminium phosphate gel adjuvant; n=178) or 0.5 mL of the pandemic vaccine and 0.5 mL of the seasonal trivalent vaccine (Fluval AB, a trivalent inactivated whole-virion influenza vaccine; n=177). All vaccinations were done by specific study personnel, who did not take part in the assessment of safety or immunogenicity. Co-primary objectives were safety and immunogenicity by haemagglutinin inhibition testing. All analyses were done according to a pre-established analysis plan. This study is registered with ClinicalTrials.gov, number NCT01010893. FINDINGS: Two participants receiving the pandemic vaccine only (group 1) and one receiving pandemic and seasonal vaccines (group 2) were lost to follow-up. Participants in both groups developed antibody responses against the pandemic influenza A H1N1 virus (group 1: seroconversion for adults 74.3%, 95% CI 64-6-82.4 and for elderly people 61.3%, 49.1-72.4; group 2: 76.8%, 67.2-84.7 and 81.8%, 71.4-89.7, respectively). Single doses of 6 microg fulfilled European Union and US licensing criteria for interpandemic and pandemic influenza vaccines. Simultaneously, participants in group 2 developed the immune responses needed for licensing for all three seasonal strains in the seasonal vaccine for the 2009-10 season. All adverse events were rare, mild, and transient; the most frequent were pain at injection site (eight cases in group 1 vs 18 in group 2) and fatigue for 1-2 days after vaccination (three vs five cases). INTERPRETATION: The present pandemic vaccine is safe and immunogenic in healthy adult and elderly patients, and needs low doses and only one injection to trigger immune responses to comply with licensing criteria. It can be safely co-administered with the 2009-10 seasonal influenza vaccine. FUNDING: Omninvest, Hungary.

Comparative analysis of diagnostic probability estimates of some common diagnoses among family doctors, medical residents, and medical students reveals negative correlation between age and estimate of chronic obstructive pulmonary disease (COPD).

BACKGROUND: Patients with their given complaints and symptoms expect certain diagnoses to be estimated with the same probability when seen by different family doctors. These estimations showed extreme variation among family doctors in Switzerland. The present study investigated whether there is any difference in the probabilities of the same diagnoses given by Hungarian doctors and, if so, what the responsible factors are. Estimates given by specialists, residents of family medicine, and medical students were also compared. MATERIAL/METHODS: In this cross-sectional study, 484 family physicians, 124 medical residents, and 148 medical students completed a questionnaire that assessed the diagnostic probability of six clinical scenarios. RESULTS: Medians and ranges of probability were almost the same in both countries. Significant negative correlation was observed between age and the estimation of COPD among the family physicians (Spearman's r=-0.231, p<0.001). This correlation was even more expressed in men and was independent of gender, previous specialization in internal medicine or pulmonology, and the location of practice. Family physicians rated the probability of myocardial infarction higher than the residents (p<0.01). They also rated the probability of congestive heart disease higher than the medical students (p<0.001). Women residents and students gave higher estimates in almost all clinical settings than did men. CONCLUSIONS: Diagnostic estimates of the same clinical scenarios vary widely among Hungarian family doctors, residents, and medical students. The independent inverse relationship between the doctor's age and his/her estimate of the probability of COPD underscores the need to intensify education on this disease.

ApoE-Targeting Increases the Transfer of Solid Lipid Nanoparticles with Donepezil Cargo across a Culture Model of the Blood-Brain Barrier.

Pharmacological treatment of central nervous system (CNS) disorders is difficult, because the blood-brain barrier (BBB) restricts the penetration of many drugs into the brain. To solve this unmet therapeutic need, nanosized drug carriers are the focus of research efforts to develop drug delivery systems for the CNS. For the successful delivery of nanoparticles (NPs) to the brain, targeting ligands on their surface is necessary. Our research aim was to design a nanoscale drug delivery system for a more efficient transfer of donepezil, an anticholinergic drug in the therapy of Alzheimer's disease across the BBB. Rhodamine B-labeled solid lipid nanoparticles with donepezil cargo were prepared and targeted with apolipoprotein E (ApoE), a ligand of BBB receptors. Nanoparticles were characterized by measurement of size, polydispersity index, zeta potential, thermal analysis, Fourier-transform infrared spectroscopy, in vitro release, and stability. Cytotoxicity of nanoparticles were investigated by metabolic assay and impedance-based cell analysis. ApoE-targeting increased the uptake of lipid nanoparticles in cultured brain endothelial cells and neurons. Furthermore, the permeability of ApoE-targeted nanoparticles across a co-culture model of the BBB was also elevated. Our data indicate that ApoE, which binds BBB receptors, can potentially be exploited for successful CNS targeting of solid lipid nanoparticles.

Presence of Titanium and Toxic Effects Observed in Rat Lungs, Kidneys, and Central Nervous System in vivo and in Cultured Astrocytes in vitro on Exposure by Titanium Dioxide Nanorods.

BACKGROUND: Non-spherical titanium dioxide (TiO2) nanoparticles have been increasingly applied in various biomedical and technological fields. Their toxicological characterization is, however, less complete than that of roundish nanoparticles. MATERIALS AND METHODS: Anatase form TiO2 nanorods, ca. 15x65 nm in size, were applied to cultured astrocytes in vitro and to the airways of young adult Wistar rats in vivo in 5, 10, and 8 mg/kg BW dose for altogether 28 days. Presence of nanorods and cellular damage was investigated in the astrocytes and in rat lungs and kidneys. Functional damage of the nervous system was studied by electrophysiological methods. RESULTS: The treated astrocytes showed loss of viability without detectable apoptosis. In rats, TiO2 nanorods applied to the airways reached the blood and various organs including the lungs, kidneys, and the central nervous system. In lung and kidney samples, nanorods were observed within (partly damaged) phagolysosomes and attached to organelles, and apoptotic cell death was also detected. In cortical and peripheral electrophysiological activity, alterations corresponding to energy shortage (resulting possibly from mitochondrial damage) and astrocytic dysfunction were detected. Local titanium levels and relative weight of the investigated organs, apoptotic cell death in the lungs and kidneys, and changes in the central and peripheral nervous activity were mostly proportional to the applied doses, and viability loss of the cultured astrocytes was also dose-dependent, suggesting causal relationship of treatments and effects. CONCLUSION: Based on localization of the visualized nanorods, on neuro-functional changes, and on literature data, the toxic mechanism involved mitochondrial damage, oxidative stress, and apoptotic cell death. These indicate potential human toxicity and occupational risk in case of exposure to rod-shaped TiO2 nanoparticles.

A reduced-dose seasonal trivalent influenza vaccine is safe and immunogenic in adult and elderly patients in a randomized controlled trial.

With the recent pandemic of influenza A (H1N1) and vaccine shortages, there has been considerable interest in developing influenza vaccines with reduced doses, allowing for increased production capacity. Here we report a prospective, randomized, double-blind, single-center clinical trial of a reduced-dose whole-virion inactivated, adjuvanted influenza vaccine in adult and elderly volunteers. A total of 234 subjects, including 120 adults (18 to 60 years of age) and 114 elderly subjects (>60 years of age) were enrolled to receive either 6 µg or the conventional 15-µg dose of seasonal trivalent influenza vaccines. The subjects were followed for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition testing. The subjects developed antibody responses against the seasonal influenza A virus H1N1 and H3N2 strains, as well as the seasonal influenza B virus included in the vaccines. Single doses of 6 µg fulfilled licensing criteria for seasonal influenza vaccines. No significant differences in rates of seroconversion or seroprotection or in geometric mean titers were found between the two dosage levels. All adverse events were rare, mild, and transient. We found that the present reduced-dose vaccine is safe and immunogenic in healthy adult and elderly subjects and triggers immune responses that comply with licensing criteria.